I. Tissue injury incident to chemotherapeutic agents.
Anthracycline antibiotics, one of which is the well-known chemotherapeutic agent doxorubicin, is a class of drugs widely used in anticancer chemotherapy with particular efficacy against lymphoma, leukemia, myeloma, breast cancer, and small cell lung carcinoma. Although the potential of these drugs to kill cancer cells in vitro has been almost unlimited, the in vivo applications have been somewhat limited due to the agents' severe side effects. The seventy of the side effects has been observed in patients who were accidentally exposed to high single or total (cumulative) doses, or in laboratory animals.
If a patient receives an accidentally high dose of doxorubicin, i.e., above 100 mg/m.sup.2, he may die in a few hours because of cardiac arrhythmia, or in a few days due to severe necrotizing general mucositis. A survivor may expect irreversible aplastic anemia within a few weeks, or chronic heart failure after a few months. Conventional therapeutic protocols allow individual doses of 40-60 mg/m.sup.2 in repeated doses until 550 mg/m.sup.2 total dose is reached, usually within 6-12 months. Accumulation of doxorubicin total dose beyond this safe range increases the risk for development of chronic irreversible heart failure.
Doxorubicin affects several targets inside heart myocytes and the result is visible as swelling and decomposition of myofibriles, vacuolization and granulation inside cytoplasm, interstitial edema, activation of fibroblasts, necrosis of myocytes and their restitution with fibrotic tissue. Six weeks after damage, the scar tissue appears, and this is of course incompatible with heart muscle function and signs of cardiac failure become progressively more pronounced. In some cases, irreversible cardiac damage can appear five years after successful cancer treatment.
Theoretically, heart damaged patients whose cancer is in remission have the escape option of heart or heart/lung transplantation. These transplantation options have recently been recognized as an important available method to treat doxorubicin-induced irreversible cardiomyopathy in children (Luthy, A., et al., "Orthotopic heart transplantation: an efficient treatment in a young boy with doxorubicin-induced cardiomyopathy," J. Heart and Lung Transplantation, 11:815-816 (1992)). As a practical matter, however, the cumulative toxicity of doxorubicin has meant that it has not been administered in high enough amounts to achieve the dramatic cancer remissions of which it would otherwise be capable.
Enormous efforts have been devoted to find a way to prevent, to postpone or to cure doxorubicin cardiotoxicity, and about one hundred drugs have been proposed to date for this purpose. However, either because of their own side effects or because of their action to reduce doxorubicin's antiproliferative effect, only a few have reached clinical trials and none has been accredited as the final solution to the problem.
Doxorubicin is believed to act primarily against DNA, but also generates free oxygen radicals in both normal and cancerous cytoplasm and antimetabolic action inside mitochondria. Suppression of oxygen free radical damage of cells can prevent, alleviate or reverse other diseases as well.
II. Tissue injury incident to free oxygen radicals.
Free oxygen radicals cause cell damage primarily due to lipid peroxidation and other degenerative intracellular biochemistries. Free oxygen radicals thus figure in the etiology of many tissue-injury type diseases, including but not limited to the ischemic diseases-myocardial infarction, stroke, and thrombosis--as well as hypoxia, hyperthermia, the various radiation injuries and certain obesity etiologies. Although different investigators have endeavored to find a protective agent for these types of cell damage, apart from the efforts to overcome doxorubicin carcliotoxicity and other side effects, these efforts have heretofore been disappointing at best.
Accordingly, a need remains for an active agent which can protect cells from tissue injury caused by chemotherapeutic agents, ischemia and radiation. More importantly, a need remains for an active agent which can protect normal cells from injury while at the same time permitting an anticancer agent such as doxorubicin to exert its potent, antiproliferative effect on the tumor cells.